The role of mast cell activation in neuroinflammation

中枢神经系统（CNS）的炎性疾病与严重的身体和精神损害有关，因此对患者和医疗保健系统都是一个巨大的负担。多发性硬化症（MS）是一种典型的自身免疫性疾病，是一种中枢神经系统的炎症性疾病，在世界范围内约有1，000，000例患者。与MS相反，阿尔茨海默病（AD）是老年人最常见的痴呆症，也是致残和死亡的重要原因，几十年来一直不被认为是炎症性疾病。然而，越来越多的证据表明，AD也是由免疫机制驱动的。在这里提出的项目中，我们希望阐明肥大细胞（MC）的激活在MS和AD发病机制中的作用。在实验性自身免疫性脑炎（EAE）中，MS的模型，Toll样受体（TLR）介导的免疫应答已被证明通过衔接分子MyD88对疾病的严重程度产生关键影响，并且有数据表明MC也促进疾病。使用EAE小鼠模型，我们的目的是测试我们的假设，TLR介导的MCs的激活集中参与MS的启动和进展。基于MS和AD的发病机制之间存在相似性的假设，我们还想研究先天免疫在AD中的作用，通过使用转基因小鼠模型，以及是否先天免疫激活的MCs在这里起着核心作用。最后，我们希望评估MCs的药理学抑制在这些疾病中的作用。

Inflammatory diseases of the central nervous system (CNS) are associated with severe physical and mental impairments and are therefore a great burden for both patients and Health Care systems. Multiple Sclerosis (MS) is an inflammatory CNS disease affecting about 1,000,000 patients world wide, and is viewed as a classical autoimmune disease. In contrast to MS, Alzheimer's disease (AD), the most frequent dementia of the elderly and an important cause of disablement and death, has not been regarded as an inflammatory disease for decades. However, evidence is accumulating that AD is also driven by immune mechanisms. Within the projects proposed here we want to elucidate the role of activation of mast cells (MCs) in the pathogenesis of MS and AD. In experimental autoimmune encephalitis (EAE), a model for MS, Toll-like Receptor (TLR)-mediated immune responses have been shown to crucially affect severity of disease via the adaptor molecule MyD88, and data is available that MCs promote disease as well. Using a mouse model of EAE, we aim to test our hypothesis that TLR-mediated activation of MCs is centrally involved in both initiation and progression of MS. Based on the hypothesis that similarities exist between pathogenesis of MS and AD, we furthermore want to study the role of innate immunity in AD by using transgenic mouse models, and whether innate immune activation of MCs plays a central role here. Finally, we want to evaluate the effect of pharmacological inhibition of MCs in these diseases.